Effects and mechanisms of transcutaneous auricular vagus nerve stimulation on post-stroke cognitive impairment in animal studies: a systematic review and meta-analysis

Background Post-stroke cognitive impairment (PSCI) substantially undermines rehabilitation adherence and poses a major obstacle to functional recovery. Transcutaneous auricular vagus nerve stimulation (taVNS), a noninvasive neuromodulation technique, has the potential to improve cognitive function, as demonstrated in various clinical and preclinical studies. Against this backdrop, we performed a meta-analysis of taVNS in experimental stroke models to quantify its cognitive benefits and probe the biological mechanisms involved in its effects. Methods We systematically searched databases, including PubMed, The Cochrane Library, Embase, and Scopus, to identify controlled animal studies evaluating taVNS in PSCI models. Following eligibility screening, five studies were selected for final synthesis. The primary cognitive outcomes comprised escape latency in the Morris water maze and the Barnes maze. Data extraction was performed independently by two investigators, and statistical analyses were performed using Review Manager 5.4 software. Results Five RCTs involving 158 rodents were analyzed in this study. The meta-analysis revealed that taVNS significantly improved memory function in PSCI animals (SMD = 1.85, 95% CI: 1.06 to 2.64, p < 0.01, I 2 = 57%) and learning ability (MD = − 6.38, 95% CI: − 8.87 to − 3.89, p < 0.01, I 2 = 0%) and reduced modified neurological severity scores (MD = − 1.08, 95% CI: − 1.63 to − 0.52, p < 0.01, I 2 = 38%). Mechanistically, taVNS significantly elevated acetylcholine levels (SMD = 1.57, 95% CI: 0.85 to 2.30, p < 0.01, I 2 = 0%), inhibited neuronal apoptosis (SMD = 2.29), and promoted angiogenesis (SMD = 1.63). Sensitivity analysis confirmed the robustness of the primary outcomes. Conclusion This study provides preclinical evidence confirming that taVNS can effectively improve cognitive deficits in PSCI animal models. The enhancement of Ach levels, inhibition of neuronal apoptosis, and promotion of vascular repair may be related to the non-neuronal cholinergic system (NNCS), anti-inflammatory, and antioxidant stress mechanisms. However, as only a few studies were included, more high-quality animal experiments are needed in the future to develop standardized interventions and further explore the molecular mechanisms underlying these effects. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261329420 .